Since the pathology of Alzheimer's (AD) appears to begin years before the symptoms and signs of the disease, it is critical to have biomarkers that can identify individuals at high risk to target them for therapies to delay/prevent the disease. Identification of antecedent biomarkers would allow us to identify individuals likely to have AD pathology but who are still cognitively normal, a group in which targeted therapies would likely have the greatest clinical impact. A few AD biomarkers have been identified that may distinguish individuals with clinical disease (dementia) from those who are cognitively normal. However, there are no validated antecedent biomarkers for AD pathology in presymptomatic individuals. We hypothesize that changes taking place in the brain during the development of AD pathology is reflected in the cerebrospinal fluid (CSF), and that these biochemical changes in CSF can be detected in cognitively normal individuals many years prior to the onset of cognitive decline, and thus can be used as antecedent biomarkers predictive of future dementia. Although biomarker validation will require longitudinal clinical assessment of individuals over many years to determine who ultimately develops dementia, as a first step, we plan to test whether putative CSF biomarkers can discriminate cognitively normal individuals (age 45-75) as a function of AD risk defined by family history of AD or apoE genotype, the strongest genetic risk factor for AD. We have begun banking a unique collection of CSF samples to measure hypothesized CSF AD biomarkers (i.e., Abeta42, tau, p-tau181, sulfatide, LP-associated Abeta40/Abeta42 ratio), and propose to begin to determine if these biomarkers are predictive of future dementia. Sensitive, unbiased proteomics techniques (i.e. two-dimensional difference gel electrophoresis and multidimensional liquid chromatography-mass spectrometry) will also be used to determine if there are alterations in the level of specific proteins/peptides in CSF as a function of AD risk. Correlation of CSF measures with cognitive and neuroimaging variables investigated by others in this proposal will also be investigated.